A number of genetic diseases, such as xeroderma pigmentosum and Cockayne syndrome involve defects in the processing of DNA damage. The role of DNA repair processes in cancer prevention is widely appreciated, but is also becoming clear that there is an important role for DNA repair in normal development. This requirement is proposed to be related to DNA damage from reactive oxygen species generated during metabolism. The broad range of this proposal is to elucidate the molecular mechanisms involved in repair of these oxidative lesions and to investigate the role of the human DNA repair protein, XPG in base excision repair (BER) of oxidative damage. The hypotheses to be tested are (1) that the central role of XPG in repair of oxidative damage is mediated by its protein-protein interactions with BER enzymes and with proteins involved in other repair pathways. And (2) that transcription- coupled BER of oxidative damage which requires XPG proceeds involved in other repair pathways. And (2) that transcription-coupled BER of oxidative damage which requires XPG proceeds by a DNA polymerase beta independent pathway, with the possible involvement of XPG in the selection of the repair patch pathway. Protein-protein interactions between XPG and other proteins will be tested by Far western analysis and candidate pathway. Protein-protein interactions between XPG and other proteins will be tested by Far western analysis and candidate proteins will be tested for an effect on their activities in the presence of XPG. The involvement of DNA polymerase beta in transcription coupled BER will be tested with the use of cell lines that lack DNA polymerase data.